Process for synthesizing ring compounds



May 7, 1946. c. B. PoLLARD ET A1. 2,400,022

PROCESS FOR SYNTHESIZING RING COMPOUNDS Filed July l5, 1942 Patented May 7, 1946 I l im2,400,022

- UNITED ASTATES PATENT PROCESS FOR SYNTHESIZING RING l OLIPOUNDS Icash rougi-a and' Leland J. maken, Gainesville, Fla., assignors to the Board of Commissinners yoi' State Institutions, Tallahassee, Fla.

y Application July 15, 1942y Serial No. 451,048A 4 claims. .(cl. 26o-ass) The present invention relates to a processfcr lar application to the production of such com pounds as piperazine and substituted piperazines.

'I'he invention has for its object the provision of'an emcacious process for the preparation of ring compounds such as piperazine and sub-stituted piperazlnes through the medium of ring closure from economic starting materials whereby such desirable products can be efiiciently and economically produced. These products are highly advantageous as intermediates in the production of synthesized compounds, more particularly in the pharmaceutical eld, and are particularly useful as intermediates inthe production of pyrazin and substituted pyrazins. Piperazine is. additionally of special value in the identiiication of fatty acids in analytical and research work.

The basic reaction of the present invention involves the splitting oil of water from compounds of the following general formula:

wherein the OH radical is hydroxyl in nature, the terminal NH group is typically amino, and X `is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and alkaryl.

AS applied to the direct preparation of piperazine, the reaction may be exemplied as follows:

The reaction is eifected in the presence of a suitablel catalyst under conditions which will be more speciiically hereinafter pointed out. The basic reaction is the same when producing substituted piperazine `and in this instance may be exemplified as follows:

in which R represents hydrogen or an alkyl, aryl,

'synthesizing ring compounds and has 4particuarallcyl, or alkaryl group or groups or any combination thereof. Since the four carbon atoms have eight positions permitting substitution, it is obvious that the number of substituent groups can- 5 not exceed eight. l

As above indicated, the source material for the preparation of unsubstituted piperazine is hydroxyethyl ethylenedlamine. v l l.

'I'he starting materials for the preparation l" of substituted piperazines are substituted hydroxyethyl ethylenediamines. These amino-alcohols are readily prepared by the reaction of an ethylene oxide or a substituted ethylene oxide with e. 1,2-diamine (ethylene diamine or a 1,2- diamine with substituents) Many o! these materials are available commercially,- such as the following:

(I) Ethylene oxide (II) Propylene oxide (m) Isobutylene oxide (IV) Phenylethylene oxide (V) Ethylene diamine (VI) Propylene diamine Hocmcmrmcmoncm and mNcHloncH Nncmomon each of which upon ring closure yields 2-methylpiperazine.

Propylene oxide plus ethylene diamine 2-hydroxypropyl ethylene diamine. which upon ring closure yields 2methylpiperazine.

Propylene oxide plus propylene diamine V two isomeric 2-hydroxypropyl propylene diamines,

which upon ring closure yield a mixture of approximately 2,5-dimethylpiperazine and 50% 2,6-dimethylpiperazine, separable by fractionation.

Isobutylene oxide plus ethylene diamine-N- 5o (2-methyl-2-hydroxypropyl) ethylene diamine. which upon ring closure yields 2,2--dimethyl-y piperazine.

Isobutylene oxide plus propylene diamine-two isomeric N -(2methyl 2 hydroxypropyl) pro pylenediamines, which upon ring closure yield a mixture of 2,2,5-trimethylpiperazine and 2,216- trimethylpiperazine, separable by fractional distillation.

Phenylethylene oxide-plus ethylene diamine-r N-(2-hydroxy-2-phenylethyl) -ethylene diamine,

which upon ring closure yields 2phenylpipera zine.

Phenylethylene oxide plus propylene diamine two isomerlc N (2 hydroxy 2 phenylethyl) propylene diamines, which upon ring closure yield a mixture of 2,2-dimethyl-5-phenylpiperazine and 2,2-dimethyl-6-phenylpiperazine.

A further extensive series of substituted ethylene diamines is available in the nitroparamn industry. These diamines are produced by the following series of reactions:

Nitroparaiiin-i-chlorine-i-sodium hydroxidechloronitroparaiiin Chloronitroparaiiin+nitroparafiin+sodium hydroxidedinitroparamn.

which on reduction yields the corresponding diaminoparaflin. Forexample:

O-Na

sodlul uit of nitroethane Nitroetllane CH;CH(C1)NO: NaCl l-chlol-onitroethane Illustrative or the olamlnes available from the three nitroparailins (nitroethane. 1-nitropropane, and z-nitropropane) are the following:

(VII) 2,8-diaminobutan (VIII) 3,4-

(IX) 2,3-diamino-2-dimethylbutane and the three lmsymmetrical diamines:

(X) 2.3ediaminopentane (XI) 2.3-diamino-2-.methylpentane (XII) 2,3-diamino-2-'methylbutane In addition. the use of nitromethane with the above mentioned nitroparamns yields:

(XIII) Lfdiaminobutane and (XIV) 2,3diamino-2-methylpropane These ring closures take place under the same conditions under which unsubstituted piperazines are produced. Infactthe presenceofalkylsubstituents in a linear reactive molecule has often been found to facilitate ring closure.

While the foregoing are illustrative of substituted piperaslnes readily producible from available materials. it will be appreciated that numerous other ethylene oxides may be prepared. While it is desirable to use a symmetrical ethylene diamine. i. e., one which has identical substituents on the two carbon atoms bearing amino groups, when the oxide reactant is unsymmetrical, this is not absolutely essential.

As hereirlbefore pointed out, the basic reaction underlying the invention is one of ring closure accompanied by a splitting off of water. The reaction is eil'ected in the presence of a suitable catalyst under appropriate conditions of temperature and pressure.

The following are representative of catalysts which are operative for carrying out the process: The metals of group III. group VIII, and subgroup B in groups I and II of the periodic table (with the exception of mercury) and their oxides, as well as the oxides of the elements below carbon in group IV of the periodic table.

It is to be understood that any form of the element or any compound which yields one of the above enumerated catalysts under the reaction conditions which prevail in carrying out the process may be used in place of the particular metal oxide or metal enumerated as effective as a catalyst for the reaction since in such instances the catalyst is, so to speak, produced in situ.

The catalysts are preferably employed in'i'inely divided form and maybe deposited upon a porous material. such, for example. as diatomaceous earth or activated charcoal, although they are frequently employed in the form of a suspension I 80 in the reactant or the reactant and a suitable diluent. In some instances it is found desirable to employ a mixed catalyst, such, for example, as copper chromite, rather than copper oxide for the reason that the mixed catalyst is somewhat Il more stable than the simple oxide. Furthermore,

mixed catalysts are often more readily obtainable in the desired finely divided state.

0r the above catalysts. we have found Raney nickel, copper chromite. cupric oxide, Activated 40 Alumina, reduced iron, and silica iiel to be particularly eifective, and we, therefore. give them as our preferred catalysts.

When employing such catalysts as silica gel and Activated Alumina, it is advantageous to prepare them by methods designed to yield catalytic material. catalysts so prepared often contain a small amount of combined water. Thus silica gel, which consists mainly of silicon dioxide, is superior to pure silicon dioxide as a catalyst in carrying out the instant process. However, since silica gel is a form of silicon dioxide, it is intended to be included in the classification of catalysts as set forth above.

It has been found desirable to employ a diluent for the particular reactants used in the process. The function of the diluent is primarily to reduce the viscosity of the reactant and to facilitate contact thereof with the catalyst. 'I'he catalyst is usually introduced to the diluted reactant with stirring so as to form a suspension and is maintained in suspension by mild agitation throughout the process. 'I'he diluent must, of course. be one which is capable of reducing the viscosity of the reactant and which is inert to the desired reaction under the conditions of operation. and it must have an appropriate boiling range. The diluent may, therefore, vary, depending upon whether the process is conducted under atmospheric pressure or under superatmospheric pressure and likewise depending uponl the character of the product to be produced, that is, whether anhydrous or hydrated.

When operating under a superatmospheric pressure of the order of 500 pounds per square inch, dioxane has been found to be a very advantageous diluent. particularly because it forms a low-boiling aneotroplc mixture-with the water released from the reactant during the process and l facilitates the removal of the waterirom the reaction product, enabling the production of anhyl drous piperazine. Other exemplary low-boiling diluents are the following:

Tetramethylene oxide, B. P. 65 C., l Ethylene glycol dimethyl ether, B. P. 82-3" C. Diethylene glycol dimethylether, B. P. 160 C.

When operating at low pressures ofthe order of atmospheric pressure and in the production oi.' a v Diethylene glycol dietlrvl ether (diethyl carbitol) B. P. 188 C. Tetraethylene glycol dimethyl ether, B. P. 276 C.

- Tetraethylene glycol diethyl ether, B. P. 1324 C./4 mm.

While the employment of a diluent is desirable and is believed to minimize side reactions, it lis not essential to the attainment of the ring closure reaction of the invention.

The process may be conducted either batchwise or continuously, and to facilitate an understanding of the operation oi the invention, we illustrate diagrammatically one suitable apparatus for carrying out the invention. In the accompanying drawing there is shown in side elevation an apparatus suitable for batchwise practice oi the process.

Referring to the drawing, there is disclosed a battery of suitable reaction chambers at I. and 2. It is to be understood that any suitable number of such 'reaction chambers may be employed. These reaction chambers I 'and 2 are arranged in parallel. 'Ihe charging material for the process,

which constitutes a suspension ot the selected catalyst in either the diluted or undiluted reactant, is supplied through the line 3 and passed either through line l and valve 5 `to reaction chamber I or, alternatively, through line 6 and valve 1 to reaction chamber 2. The reaction chambers are suitably heated either by being disposed in a suitable furnace or through the me- -dium of. electrical resistance elements (not shown) so as to maintain the required temperature conditions for the reaction.

Each reaction chamber is additionally provided with an appropriate agitator which may take the form of a conventional motor-driven bladed stlrrer or rocking device. When the charge has been supplied tothe reaction chamber, the same is closed on and the charge is heated to the required temperature and maintained at such temperature with agitation for a time period appropriate for the particular reactant and catalyst -being employed.

When a superatmospheric pressure is imposed, it may be provided by introducing to the reaction chamber containing the charging material an inert gas such as nitrogen or hydrogen, and it is to be understood that suitable connections are provided for this purpose and that the reaction chambers are constructed to be operated under appropriate superatmospheric pressure conditions.

'Ihe time period of the reaction will vary. de-

pending upon the particular reactant, the catalyst, andthe temperature and pressurel conditions employed. However', a period of around three hours has been found adequate for most operations. u r u Y When the reaction has proceeded to the desired point, the reaction mixture is drawn oil.' trom the reaction chamber I through valve 8 and line i or, alternatively, i'rom reaction chamber z through valve III, and in either event passes through line II into a suitable illter I2 wherein the suspended catalyst is separated from the reaction mixture.

From the illter I2 the nitrate passes through line I3 and valve I 4 into distillation chamber Il.

'I'he chamber II may be heated to the requisite temperature by any sintable' means, for example, through the'medium of appropriate electrical resistance elements.

vapors released from thev reaction mixture, which now contains the water given up as a result of the reaction which has occurred in the reaction chamber, pass from distillation chamber I5 into the iractionating column I6 wherein an appropriate reilux ratio is maintained to facilitate separation of thecomponents oi the reaction mixture. For example, when dioxane is employed as the diluent, it' forms, together with the water released during the reaction, an azeotropic mixture which boils at approximately 87 C.

By suitable control of the iractionating column I8 during the initial period of distillation oi' the batch reaction mixture, the azeotropic mixture may be effectively separated from the reaction product and residual reactant material. From reiiux column I6 the vapors pass via line I1 to condenser I8 from which the distillate maybe in whole or in part drawn oft through the line I8 controlled by the valve 20 or in part recycled to the top oi the fractionating tower I6 through line 2| controlled by valve 22.

The process is sometimes accompanied by-the formation of small amounts of ammonia, and this may be vented from the vapor line I1 through i a suitable cooler 23 which permits the ammonia gas to pass out via line 2l and valve 2l. Toward the end of the distillation operation, when the product is being taken overhead, it is sometimes desirable to maintain a moderate vacuum on the distillation system. 'I'his may be done by drawing a suitable vacuum on the line 26 controlled by valve 21.

The residual reactant is withdrawn from the distillation vessel `I5 through line 28 controlled by valve 29.

In some instances, more particularly when the diluent is of a high boiling characterl and the piperazine is taken overhead from the distillation system in admixture with water, such admixture may be passed through the line In controlled by the valve II into the dehydrating tower 32. It will be borne in mind that when the piperazine i is being distilled over from ythe distillation vessel I5, the condenser I8 will at al1 times be maintained at a temperature slightly above the melting point oi piperazine, i. e.. at a temperature of approximately C. 'I'here Vis introduced to the dehydrating column I2, through the line controlled by the valve Il, a suitable dehydrating agent, such, for example, as benzene. The tower I2 is appropriately heated as by a steam coil 35. The benzene and water form a low-boiling anectropic mixture in the dehydrating column 32 which may be fractionated from the higher boiling benzene and piperazine.

The benzene and water vapors pass out from the tower 92 through Iine 99. and any ammonia which has been can'ied over with the piperazine and water mixture may be vented through the cooler 81, line 39, and valve 39. Ai'ter being condensed in condenser 40, the condensed benzene and water vapors pass into an' appropriate separator 4I, from the bottom of which the water is withdrawn through line I2 and valve 43, from the top of which the benzene may be recycled through line 44 back to the top o! the dehydrating column 92.

The operation of the dehydrating column 32 may be adjusted to yield pure anhydrous piperazine or any desired concentration of piperazine in benzene as the product which is withdrawn through line 45 controlled by valve 46. In the event the piperazine is drawn oi! in solution in benzene from the bottom of tower 32, pure piperazine may be recovered by crystallization on cooling. The amount of benzene in the column remains nearly constant; and in'the event the piperazine is drawn on in solution in benzene,f

erable range lying between 200 C. and 300 C. The particular temperature within the stated range should be so selected as to keep undesirable side reactions and decompositlons of the reactant at a minimum. While the foregoing constitutes a general illustration of the adaptation of the process, it is desired to point out that in some instances, notably where the reaction is eilfected at low pressures of the order of atmospheric pressure and with relatively high-boiling diluents, it is advantageous to conduct the reaction Awith renuxing.

The following constitute illustrative examples ofthe process:

Emample I In this operation 150 parts of hydroxyethyl f etnyienedmmme, zoo parte of dioxane and 5 the loss oi benzene is compensated by addition of benzene, suitably by means of line 39. 'I'he column operation is suitably controlled by varying the heat added by coil 3l and by adjusting the rate of withdrawal of liquid through line 45.

Assuming that dioxane is used as the diluent and that anhydrous piperazine is the desired reaction product, the reaction mixture is treated in the distillation system by initially maintaining the same at an appropriate temperature to drive oir the dioxane-water azeotropic mixture, the reiluxing column I6 being so controlled as to reflux back materials of higher boiling point. The dioxane-water azeotropic mixture is condensedA in condenser I9 and drawn oi through line I9, from which it may be appropriately treated to eiIect separation of the water from the dioxane and the dioxane recovered for reuse.

After the dioxane-water azeotropic mixture has been separated from the reaction mixture, the temperature in distillation chamber I 5 is elevated so as to drive olf the pure dioxane diluent which in like manner is drawn ofi through line I9 and recovered for reuse. When the dioxane diluent has been separated from the reaction mixture, the temperature is again elevated so as to drive oil from the residual reactant the pure anhydrous piperazine which in like manner is drawn olli through the line I9 and recovered as the desired product of the process. 'I'he residual reactant is then drawn oil? from the distillation chamber.V I5. Any unreacted amino-alcohol or substituted amino-alcohol may be recovered for reuse in the process.

In those instances where a high-boiling diluent is employed, such, for example, as diethyl car- `bitol which boils at 188 C., the operation of the distillation system is obviously somewhat different in that instead of rst distilling over an azeotropic mixture followed .by taking overhead the diluent and nally the piperazine, the distillation system is operated so as to take overhead the mixture of piperazine and water. In this instance, instead of taking ofi' the respective materials direct from condenser I 9 through line I9, the mixture is passed through line 30 to the dehydratlng column 32 where separation is effected as hereinbefol'e described.

The temperature at which the reaction may be effected will vary depending upon the particular reactant and catalyst employed. Generally speaking, the temperature should lie within the range of from 175 C. to 325 C. with the prefparts of palladium on activated charcoal catalyst were prepared as a suspension and heated together in a closed reaction vessel to a temper-' ature of 225 C. The mixture was mildly agitated for six and one-half hours, during which time the temperature gradually rose. reaching a maximum of 246 C. at the time yagitation was stopped and heating discontinued. The product was then cooled and removed from the reaction vessel. The catalyst was separated from the reaction mixture by lltration. The reaction mixture was then separated by fractional distillation. A yield of 13% of solid piperazine was obtained based on the hydroxyethyl -ethylenediamine used. 'I'he product boiled within the range of 140 to 150 C. By distillation of the residual reactant at reduced pressure, 49% of the hydroxyethyl ethylenediamine used as a starting material was recovered.

` Example 1I In this operation parts of hydroxyethyl ethylenediamine was mixed with 400 .parts of dioxane and l0 parts of Raney nickel forming a suspension in the reaction vessel. The suspension thus formed was heated in a closed reaction vessel at a temperature of 200 C. and Y ldroxyethyl ethylenediamine used was obtained.

The product boiled Within the range of to .150 C. This constituted a yield of approximately 51% of the theoretical.

' Example III In this operation parts of hydroxyethyl ethylenediamine was mixed with 200 parts of dioxane and 15 parts of Activated Alumina and agitated in a closed vessel at a temperature of approximately 300 C. for three hours. The reaction mixture was then cooled to room temperature, removed from the reaction vessel and filtered` to separate the catalyst. The catalyst was rinsed with additional dioxane which was combined with the ltrate. The reaction mixture representing the filtrate was then subjected to fractional distillation. 25 parts of piperazine, representing a yield of 20% of the theoretical. was obtained. The residue, on distillation at 5 reduced pressure. yielded l2 ol hydroxy- C. A I I cpressureofiiooibaperao. etnviethylenediamine. -g in o! nitrosen was employed in this operationrmmpu The 'u recovered :mm museum In this operation 279 parts "'of hydmlyethyl ethylenediamine and 30 parts of silica gel were mixed without a diluent andintroduced into a closed reaction vessel. The mixture was heated t approximately 300 C. and agitl'ted While maintained at this temperature for three hours. The reaction mixture was then cooled, the reaction chamber opened and -the reaction mixture removed and filtered to separate the catalyst. The

catalyst was washed with a quantity of dioxane which was combined with the reaction mixture. which was then separated by distillation, yielding 40 parts of pure piperazine. 'Ulis comtituted a yield of 17.4% of the theoretical. By distillation of the residue, there was recovered 150 parts of hydroxyethyl ethylenediamine.

Example V In this operation 150 parts of hydroxyethyl ethylenediamine was distilled and renamed with 5 parts of Raney nickel in the absence of a diluent. The evolved vapors were passed through a short rei'iux column before condensation. 'Ihe conditions were maintained such that a distillate, boiling at 100 to 140 C., were collected over a period of two hours and yuntil no more such low boiling distillate appeared. An adequate reflux ratio for this purpose was maintained dur-ing the distillation. The distillate, representing 48 parts of a semi-solid material, consisted mainly of plperazine and water. Ihe yield of piperazine was 31.6% of the theoretical.

Example VI then iractionally distilled. The Pillerazine prod-Y uct represented a 45% yield of the theoretical.

Example VII In this operation 150 parts ofv hydroxyethyl ethylenediamine was distilled and rei'iuxed with 5 parts of Raney nickel as a catalyst in the absence of a diluent using a reilux column with an outlet temperature of approximately 140 C. From the distillate collected during a period of two and onequarter hours a yield of piperazine was obtained.

Example VIII In this ioperation 150 parts of hydroxyethyl ethylenediamine was reiluxed with 150 parts of diethyl carbitol and 5 parts of Raney nickel catalyst employing a reflux column having an outlet temperature held within the range of 140 to 150 C. A yield of 34% piperazine was obtained from the distillate collected over a period of several hours.

Example IX In this operationfl parte of hydroxyethyl ethylenediamine was mixed with 1000 parts of dioxane and 30 parts of Raney nickel catalyst. The mixture was agitated in a closed reaction chamber for a period of three hours while maintained at a temperature of approximately 200 piperasine representing a 50% yield ofthe t eoretieal. `l p Example X In this operation 59 parts of NH2-hydranpropyD-ethylenediaminc was mixed with 350 parts of dioxane and 10 parts of copper chromite catalyst. The mixture-was subjected to an atmosphere of nitrogen at a pressure oi' 500 lbs.,y

per sq. in. in a closed reaction chamber. The mixture was agitated for a period of three hours while maintained at a temperature of approximately 275 C. The ,contents ofthe reaction'chamber were coolcdand the nitrogen gas released. .The reaction mixture was then illtered to separate the catalyst,following which it was fractionally.

distilled. The product represented pure Z-methylpiperazine having a boiling point of 152.8 C. This product was produced in a yield representing 50% of the theoretical.

v Example XI In this operation 108.5 parts of N- (2-hydroxy- -2-phenylethyl) ethylenediamine, 300 parts of dioxane and 20 parts of Raney nickel catalyst were charged through a closed reaction vessel. The mixture was heated to a temperature of 220 C. and agitated for a period of three hours while maintained at a temperature within the range of yields generally analogous to those given for the production of unsuitituted piperazine, 2-methylpiperazine and 2-phenylpiperazine.

The foregoing description and examples are given by way of explanation and exemplincation of the invention and are not to be construed in limitation thereof, the scope of the invention being that delined in the following claims.

Having thus described our invention, we claim:

1. A process for synthesizing piperazine comprising mixing a hydroxyethyl ethylenediamine free base with a diluent inert to the desired reaction and capable of forming a low-boiling azeotropic mixture with water, and a catalyst selected from the class consisting of the metals of group III, group Vm. and sub-group B in groups I and II of the periodic table, except mercury, and their oxides and the oxides of elements below carbon in group IV of the periodic table, subjecting said mixture to a temperature ,within the range from C. to 325 C. to eiIect ring closure of said hydroxyethyl ethylenediamlne accompanied by a splitting oifof water, removing the waterdiluent mixture by fractionation and recovering the piperazine in substantially anhydrous form.

2. A process of synthesizing ahydrocarbon substituted piperazine which comprises subjecting a free base of the general formula:

in which R representsa. hydrocarbon radical to a temperature within the range of from 175 C. to 325 C. in the presence of a solvent forming a lowboiling azeotrope with water and a catalyst selected from the group consisting of the metals of group III, group VIII, and sub-group B in groups I and II of the periodic table, except mercury, and their oxides and the oxides of elements below carbon in group IV of the periodic table. to eiect ring closure and the splitting off of water. removing the azeotropic mixture by fractionation. and then recovering the piperazine in substantially anhydrous form.

3. .A process ofsynthesizing heterocyclic ccmpounds comprising subjecting a free base conforming to the general formula:

wherein X is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and aikaryl, to a temperature within the range of from 175 C. to 325 C. in the presence of dioxane' and a catalyst selected from the class consisting of the metals of group III, group VIII. and subgroup B in groups I and II of the periodic table, except mercury, and

their oxides and the oxides of elements below carbon in group IV oi' the periodic table, and then removing the water-dioxane mixture from the heterocyclic compound by fractionation.

4. A process of synthesizing heterocyclic compounds comprising mixing a free base o! the general formula:

wherein X.is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and alkaryl, with diethyl carbitol in the presence of a catalyst selecd from the class consisting of the metals of group III, group VIII, and sub-group B in groups I and II of the periodic table. except mercury, and their oxides and the oxides of elements below carbon in group IV oi the periodic-table, and subjecting the mixture to a temperature in the range within from C. to 325 C. t0 eiIect ring closure with the splitting ofi of water to formal readily separable azeotropic mixture with the diethyi carbitol.

CASH B. POLLARD.

LELAND J. KITCHEN. 

